RESUMEN
Cryptorchidism is one of the most common congenital disorders in boys, and several genetic, hormonal, and environmental factors have been proposed as possible causes for this genitourinary defect. Genetic factors have been intensively searched, but relatively few pathogenic variants have been described. Cryptorchidism is a frequent finding in patients with RASopathies, a group of syndrome caused by mutations in genes of the Ras/MAPK pathway. Our aim was to determine whether patients with isolated cryptorchidism (IC) exhibit Ras/MAPK pathway gene variants associated with RASopathies. Two hundred thirty-nine patients with IC were recruited after orchidopexy. Determination of Ras/MAPK pathway gene variants was performed by high-resolution melting (HRM) analysis followed by sequencing. Restriction or allele-specific amplification assay was applied to (i) variant confirmation; (ii) search in healthy controls; and (iii) segregation analysis. Controls correspond to 100 healthy Chilean adults without a history of cryptorchidism. Molecular analysis showed one synonymous substitution (BRAF_p.Q456Q) in two patients and four missense substitutions (SOS1_ p.R497Q, BRAF_ p.F595L, NRAS_ p.T50I, and MAP2K2_ p.Y134C) in five patients. Our results suggest that some patients with isolated cryptorchidism, but with no evidence of dysmorphic features suggestive of RASopathies, may harbor Ras/MAPK pathway gene alterations.
Asunto(s)
Criptorquidismo/genética , GTP Fosfohidrolasas/genética , MAP Quinasa Quinasa 2/genética , Proteínas de la Membrana/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteína SOS1/genética , Adolescente , Niño , Preescolar , Chile , Variación Genética , Humanos , Lactante , Masculino , Proteínas Quinasas Activadas por Mitógenos/genética , Transducción de Señal/fisiología , Proteínas ras/genéticaRESUMEN
Cryptorchidism is the most common congenital disorder in boys, but the cause for most cases remains unknown. Patients with Noonan Syndrome are characterized by a typical face, growth retardation, congenital heart defects, learning disabilities and cryptorchidism. Copy number variations of Ras/MAPK pathway genes are unusual in patients with several clinical features of Noonan Syndrome; however, they have not been studied in patients with only one feature of this condition, such as cryptorchidism. Our aim was to determine whether patients with isolated cryptorchidism exhibit Ras/MAPK pathway gene copy number variations (CNVs). Fifty-nine patients with isolated cryptorchidism and negative for mutations in genes associated with Noonan Syndrome were recruited. Determination of Ras/MAPK pathway gene CNVs was performed by Comparative Genome Hybridization array. A CNV was identified in two individuals, a ~175 kb microduplication at 3p25.2, partially including RAF1. A similar RAF1 microduplication has been observed in a patient with testicular aplasia. This suggests that some patients with isolated cryptorchidism may harbor Ras/MAPK pathway gene CNVs.
Asunto(s)
Criptorquidismo/genética , Dosificación de Gen , Sistema de Señalización de MAP Quinasas/genética , Adolescente , Niño , Preescolar , Hibridación Genómica Comparativa , Duplicación de Gen , Genes ras , Humanos , Lactante , Masculino , Linaje , Testosterona/sangreRESUMEN
CONTEXT: The long-term effects of pure 17ß-estradiol (E2) depending on route of administration have not been well characterized. OBJECTIVE: Our objective was to assess metabolic effects of oral vs transdermal (TD) 17ß-E2 replacement using estrogen concentration-based dosing in girls with Turner syndrome (TS). PATIENTS: Forty girls with TS, mean age 16.7 ± 1.7 years, were recruited. DESIGN: Subjects were randomized to 17ß-E2 orally or TD. Doses were titrated using mean E2 concentrations of normally menstruating girls as therapeutic target. E2, estrone (E1), and E1 sulfate (E1S) were measured by liquid chromatography tandem mass spectrometry and a recombinant cell bioassay; metabolites were measured, and dual-energy x-ray absorptiometry scan and indirect calorimetry were performed. MAIN OUTCOME: Changes in body composition and lipid oxidation were evaluated. RESULTS: E2 concentrations were titrated to normal range in both groups; mean oral dose was 2 mg, and TD dose was 0.1 mg. After 6 and 12 months, fat-free mass and percent fat mass, bone mineral density accrual, lipid oxidation, and resting energy expenditure rates were similar between groups. IGF-1 concentrations were lower on oral 17ß-E2, but suppression of gonadotropins was comparable with no significant changes in lipids, glucose, osteocalcin, or highly sensitive C-reactive protein between groups. However, E1, E1S, SHBG, and bioestrogen concentrations were significantly higher in the oral group. CONCLUSIONS: When E2 concentrations are titrated to the normal range, the route of delivery of 17ß-E2 does not affect differentially body composition, lipid oxidation, and lipid concentrations in hypogonadal girls with TS. However, total estrogen exposure (E1, E1S, and total bioestrogen) is significantly higher after oral 17ß-E2. TD 17ß-E2 results in a more physiological estrogen milieu than oral 17ß-E2 administration in girls with TS.
Asunto(s)
Metabolismo Energético/efectos de los fármacos , Estradiol/administración & dosificación , Terapia de Reemplazo de Estrógeno , Síndrome de Turner/tratamiento farmacológico , Administración Oral , Adolescente , Adulto , Metabolismo Basal/efectos de los fármacos , Biotransformación , Composición Corporal/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Monitoreo de Drogas , Estradiol/sangre , Estradiol/farmacocinética , Estradiol/uso terapéutico , Estrona/análogos & derivados , Estrona/sangre , Estudios de Factibilidad , Femenino , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Parche Transdérmico , Síndrome de Turner/sangre , Síndrome de Turner/metabolismo , Adulto JovenRESUMEN
UNLABELLED: Pandemic H1N1 2009 had the highest incidence in the middle-high income area of Santiago and affected mostly school age patients. Influenza A virus (IAVs) causes systemic and most commonly non-systemic infection. Interestingly, it is able to replicate only in the presence of trypsin-like enzymes, as lung and pancreas. HYPOTHESIS: IAVs infection may trigger beta cell destruction and increase the incidence of T1DM. METHODS: A retrospective observational study of new T1DM pediatric patients from database of Clinica Las Condes between 1995 and 2012. RESULTS: From 58 patients, 44.7% were diagnosed between 2009 and 2010, coincident with the H1N1 virus outbreak. There were no differences in clinical neither metabolic parameters between those patients from the 2009-2010 period and the rest. From those patients with available antibody panel, it was negative in 30% of the 2009-2010 group vs. 12.5% of the rest of the cohort (p < 0.05). Only one 5.8 year old boy had history of H1N1 virus infection three months prior to the DM1 onset with negative antibodies. CONCLUSIONS: The temporal coincidence suggests a possible link between T1DM and H1N1 virus, might be thought to be through direct cytopathic damage. Unfortunately we could only confirm H1N1 previous infection in only one case. Prospective studies in new T1DM cases are necessary to test this hypothesis.